Merit Review Abstract: Background: Lung cancer is a major medical problem and the number one cause of cancer death in men and women in the US and worldwide. Lung cancer is a medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel and recent data shows tobacco use rates higher than that of the general public. Leading Veterans organizations (AMVETS, Disabled American Veterans, Paralyzed Veterans of America, and Veterans of Foreign Wars) have supported increased funding for early lung cancer research at the Veterans Administration. While large-scale screening trials are in progress, there are no established screening tests, and a distinct minority of patients (<25%) present with surgically curable disease (stages I and II). The cumulative five-year survival rate for lung cancer is 15%, a rate which has shown limited improvement over the last several decades. The majority of lung cancers are now diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. Improved success in decreasing lung cancer rates will rely not only on smoking prevention and cessation, but also on effective chemo-preventive strategies. Work Accomplished: Prostacyclin (prostaglandin I2, PGI2) is a naturally occurring eicosanoid that possesses anti-inflammatory and anti-metastatic properties, as well as a suppressive role in tumor growth. We have found that the balance of these eicosanoids is pivotal in lung tumorigenesis. My VA funded laboratory has focused on evaluating PGI2 as a chemo-preventive agent, and transgenic mice with selective pulmonary PGIS over-expression are chemoprotected in several distinct murine adenocarcinoma models (including both chemical and tobacco-smoke exposure). We have extended our studies to animals receiving Iloprost (an oral PGI2 analogue) and have shown similar chemoprevention. Most importantly, a recent phase II clinical tria showed oral iloprost improved endobronchial damage in former smokers. Key mechanistic studies completed during the last grant cycle have shown that the observed chemoprevention may directly result from PGI2 and iloprost activating the transcription activator PPARg (peroxisome proliferator activated receptor gamma). These findings, coupled with recent clinical studies observing a 33% reduction in lung cancer rates among Veterans taking PPARg agonists for diabetes mellitus, suggest PPARg agonists may prevent lung cancer. Proposed Research: This grant proposes to advance pre-clinical studies of PPARg agonists in a squamous cell lung cancer model and a tobacco smoke exposure model. We hypothesize that PPARg activators (iloprost and pioglitazone) will chemoprevent the development of endobronchial dysplasia and lung tumors, and will alter the tumor microenvironment by affecting inflammatory cell recruitment and phenotype. The following hypotheses will be tested: Hypothesis 1: PPARg agonists (iloprost and pioglitazone) will chemoprevent the development of squamous cell lung cancer and pre-malignant endobronchial dysplasia in a murine model of squamous cell lung cancer. Hypothesis 2: PPARg agonists will chemoprevent lung cancer and premalignant lesions in a tobacco smoke model and alter inflammatory cell recruitment and activation. PUBLIC HEALTH RELEVANCE: Lung cancer is the number one cause of cancer death in men and women in the United States and a medical priority for the Department of Veterans Affairs due to the high rates of tobacco addiction acquired by military personnel. While large-scale screening trials are being conducted, there are no established screening tests for the early detection of lung cancer, and only 16% of Veterans with lung cancer are diagnosed with surgically curable disease (stages I and II). Clinical experience has shown that the majority of lung cancers are diagnosed in former smokers, emphasizing the need for effective chemoprevention in this large, at-risk population. We propose novel experiments involving chemo-preventive agents that have been shown to improve smoking induced airway damage and are associated with lower lung cancer rates in Veteran populations. Our results will lead to a better understanding of the early stages of lung cancer and may lead to future human chemoprevention trials.